The goal of this proposal is to exploit a novel high throughput assay capable of screening hundreds of thousands of compounds for affects on replicative lifespan in the yeast Saccharomyces cerevisiae. Key aspects of aging are conserved between yeast and humans, including signaling, regulatory, and effector pathways. Yeast has been a valuable model system for the discovery and elucidation of conserved aging genes such as SIR2 and their modes of regulation, but only the surface of the field has been scratched. The screening of chemical libraries with this assay should result in the identification of compounds that affect the activities of known and as yet undiscovered cellular targets with roles in aging and lifespan. The "death of daughters" (DEAD) replicative lifespan assay provides cell-based phenotypic screen that will allow us to address an entirely new order of questions about the molecular mechanism and control of aging and lifespan. This high throughput assay will allow us to investigate the genomics of lifespan, screen chemical libraries for compounds that affect lifespan, and study the genetics of lifespan among natural populations. Preliminary studies screening a library of ~2500 compounds indicates that the DEAD assay can be performed in 384 well plates without constant shaking. When the starting DEAD cell culture is prepared and handled properly, the optical density read-out is readily controlled and highly reproducible. The aim of this proposal is to facilitate DEAD assay screening of chemical libraries in the NIH Small Molecule Repository at Molecular Libraries Screening Centers. Promising compounds can be readily assessed using other lifespan assays in yeast, worms, and fruit flies. The assay results can be easily formatted in raw and processed formats to maximize their sharing and utility to others. [unreadable] [unreadable]